Abstract
Background: Walker-Warburg syndrome (WWS) is an autosomal recessive condition characterised by congenital muscular dystrophy, structural brain defects, and eye malformations. Typical brain abnormalities are hydrocephalus, lissencephaly, agenesis of the corpus callosum, fusion of the hemispheres, cerebellar hypoplasia, and neuronal overmigration, which causes a cobblestone cortex. Ocular abnormalities include cataract, microphthalmia, buphthalmos, and Peters anomaly. WWS patients show defective O-glycosylation of α-dystroglycan (α-DG), which plays a key role in bridging the cytoskeleton of muscle and CNS cells with extracellular matrix proteins, important for muscle integrity and neuronal migration. In 20% of the WWS patients, hypoglycosylation results from mutations in either the protein O-mannosyltransferase 1 (POMT1), fukutin, or fukutin related protein (FKRP) genes. The other genes for this highly heterogeneous disorder remain to be identified. Objective: To look for mutations in POMT2 as a cause of WWS, as both POMT1 and POMT2 are required to achieve protein O-mannosyltransferase activity. Methods: A candidate gene approach combined with homozygosity mapping. Results: Homozygosify was found for the POMT2 locus at 14q24.3 in four of 11 consanguineous WWS families. Homozygous POMT2 mutations were present in two of these families as well as in one patient from another cohort of six WWS families. Immunohistochemistry in muscle showed severely reduced levels of glycosylated α-DG, which is consistent with the postulated role for POMT2 in the O-mannosylation pathway. Conclusions: A fourth causative gene for WWS was uncovered. These genes account for approximately one third of the WWS cases. Several more genes are anticipated, which are likely to play a role in glycosylation of α-DG.
| Original language | English |
|---|---|
| Pages (from-to) | 907-912 |
| Number of pages | 6 |
| Journal | Journal of Medical Genetics |
| Volume | 42 |
| Issue number | 12 |
| DOIs | |
| Publication status | Published - Dec 2005 |
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ASJC Scopus subject areas
- Genetics
- Genetics(clinical)
Cite this
POMT2 mutations cause α-dystroglycan hypoglycosylation and Walker-Warburg syndrome. / Van Reeuwijk, J.; Janssen, M.; Van Den Elzen, C.; Beltran-Valero De Bernabé, D.; Sabatelli, P.; Merlini, L.; Boon, M.; Scheffer, H.; Brockington, M.; Muntoni, F.; Huynen, M. A.; Verrips, A.; Walsh, C. A.; Barth, P. G.; Brunner, H. G.; Van Bokhoven, H.
In: Journal of Medical Genetics, Vol. 42, No. 12, 12.2005, p. 907-912.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - POMT2 mutations cause α-dystroglycan hypoglycosylation and Walker-Warburg syndrome
AU - Van Reeuwijk, J.
AU - Janssen, M.
AU - Van Den Elzen, C.
AU - Beltran-Valero De Bernabé, D.
AU - Sabatelli, P.
AU - Merlini, L.
AU - Boon, M.
AU - Scheffer, H.
AU - Brockington, M.
AU - Muntoni, F.
AU - Huynen, M. A.
AU - Verrips, A.
AU - Walsh, C. A.
AU - Barth, P. G.
AU - Brunner, H. G.
AU - Van Bokhoven, H.
PY - 2005/12
Y1 - 2005/12
N2 - Background: Walker-Warburg syndrome (WWS) is an autosomal recessive condition characterised by congenital muscular dystrophy, structural brain defects, and eye malformations. Typical brain abnormalities are hydrocephalus, lissencephaly, agenesis of the corpus callosum, fusion of the hemispheres, cerebellar hypoplasia, and neuronal overmigration, which causes a cobblestone cortex. Ocular abnormalities include cataract, microphthalmia, buphthalmos, and Peters anomaly. WWS patients show defective O-glycosylation of α-dystroglycan (α-DG), which plays a key role in bridging the cytoskeleton of muscle and CNS cells with extracellular matrix proteins, important for muscle integrity and neuronal migration. In 20% of the WWS patients, hypoglycosylation results from mutations in either the protein O-mannosyltransferase 1 (POMT1), fukutin, or fukutin related protein (FKRP) genes. The other genes for this highly heterogeneous disorder remain to be identified. Objective: To look for mutations in POMT2 as a cause of WWS, as both POMT1 and POMT2 are required to achieve protein O-mannosyltransferase activity. Methods: A candidate gene approach combined with homozygosity mapping. Results: Homozygosify was found for the POMT2 locus at 14q24.3 in four of 11 consanguineous WWS families. Homozygous POMT2 mutations were present in two of these families as well as in one patient from another cohort of six WWS families. Immunohistochemistry in muscle showed severely reduced levels of glycosylated α-DG, which is consistent with the postulated role for POMT2 in the O-mannosylation pathway. Conclusions: A fourth causative gene for WWS was uncovered. These genes account for approximately one third of the WWS cases. Several more genes are anticipated, which are likely to play a role in glycosylation of α-DG.
AB - Background: Walker-Warburg syndrome (WWS) is an autosomal recessive condition characterised by congenital muscular dystrophy, structural brain defects, and eye malformations. Typical brain abnormalities are hydrocephalus, lissencephaly, agenesis of the corpus callosum, fusion of the hemispheres, cerebellar hypoplasia, and neuronal overmigration, which causes a cobblestone cortex. Ocular abnormalities include cataract, microphthalmia, buphthalmos, and Peters anomaly. WWS patients show defective O-glycosylation of α-dystroglycan (α-DG), which plays a key role in bridging the cytoskeleton of muscle and CNS cells with extracellular matrix proteins, important for muscle integrity and neuronal migration. In 20% of the WWS patients, hypoglycosylation results from mutations in either the protein O-mannosyltransferase 1 (POMT1), fukutin, or fukutin related protein (FKRP) genes. The other genes for this highly heterogeneous disorder remain to be identified. Objective: To look for mutations in POMT2 as a cause of WWS, as both POMT1 and POMT2 are required to achieve protein O-mannosyltransferase activity. Methods: A candidate gene approach combined with homozygosity mapping. Results: Homozygosify was found for the POMT2 locus at 14q24.3 in four of 11 consanguineous WWS families. Homozygous POMT2 mutations were present in two of these families as well as in one patient from another cohort of six WWS families. Immunohistochemistry in muscle showed severely reduced levels of glycosylated α-DG, which is consistent with the postulated role for POMT2 in the O-mannosylation pathway. Conclusions: A fourth causative gene for WWS was uncovered. These genes account for approximately one third of the WWS cases. Several more genes are anticipated, which are likely to play a role in glycosylation of α-DG.
UR - http://www.scopus.com/inward/record.url?scp=26944438148&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=26944438148&partnerID=8YFLogxK
U2 - 10.1136/jmg.2005.031963
DO - 10.1136/jmg.2005.031963
M3 - Article
C2 - 15894594
AN - SCOPUS:26944438148
VL - 42
SP - 907
EP - 912
JO - Journal of Medical Genetics
JF - Journal of Medical Genetics
SN - 0022-2593
IS - 12
ER -